WNK-SPAK/OSR1-N(K)CC Signaling in the Kidney

ascending limbs and distal convoluted tubules of kidney, respectively. Several genetically-altered mice models have been created to explore the in vivo function of WNK, SPAK/OSR1 and NCC. PHAII-mutant WNK4 transgenic/knock-in mice exhibit typical PHAII phenotype with an increased phosphorylation and function of SPAK/OSR1 and NCC. On the other hand, mice with attenuated WNK4 or SPAK expression manifest Gitelman-like syndrome, the mirror images of PHAII, with a reduced phosphorylation and function of NCC. Mice with altered WNK1 expression also have abnormal blood pressure and disturbed renal Na + regulation. Polymorphisms in genes encoding WNK1, WNK4, SPAK and NCC are also associated with essential hypertension and WNK-SPAK/OSR-NCC signaling is also reported to involved in salt-sensitive hypertension. This review summarizes the important studies in the molecular pathophysiology of WNK-SPAK/OSR1- N(K)CC signaling in the kidneys from cell and transgenic animal models to human studies.